Adriamycinの細胞核への取り込み, およびDNAとの相互作用

抄録

The incorporation of Adriamycin (14-hydroxydaunomycin), a new antibiotic possessing an antitumor activity, into Ehlrich ascites tumor cell nuclei and the interaction between Adriamycin and DNA were investigated. Intraperitoneal injection of Adriamycin[³H(G)] to mice bearing Ehlrich ascites tumor demonstrated that silver grains in its autoradiogram were localized in tumor cell nuclei. The gel filtration of tumor cell chromatin over Sephadex G-25 and of chromatin digested by trypsin over Sephadex G-200 suggested that Adriamycin was bound to DNA and not to protein of chromatin. The binding of DNA and Adriamycin in vitro was supported by some physicochemical changes such as visible absorption spectrum fluorescence intensity, polarographic behavior, and possession of non-dialytic quality in Adriamycin and thermal denaturation-renaturation behavior of DNA. RNA, apurinic deoxyribonucleic acid, apyrimidinic deoxyribonucleic acid, hyaluronic acid, chondroitinsulfate, heparin, and a high concentration of AMP and TMP seeded to be bound to Adriamycin, but the physicochemical changes were not exactly the same as those induced by DNA. The quantitative investigation of interaction between Adriamycin and DNA was made by an equilibrium dialysis procedure. It was thereby found that Adriamycin was bound to DNA according to the Langmuir-type interaction and that free energy changes of binding were 8.4 kcal/mole. Calculations showed that the saturated binding site of DNA was 1 per 5.4 bases of DNA. It was suggested that more than two kinds of binding type, perhaps including hydrogen bond and ionic bond, were present in the Adriamycin-DNA complex. Adriamycin inhibited the RNA synthesis and DNA degradation by deoxyribonuclease, depending on the DNA-Adriamycin molar ratio. The formation of DNA-Adriamycin complex can be considered to be responsible for the biological effect of Adriamycin.